In nearly all animal tissues, thin barriers called basement membranes anchor outward-facing layers of cells—the linings of lungs, the top layers of skin, the insides of blood vessels—to the connective tissues that support them. Mutations disrupting any major basement membrane component are often incompatible with human life, and partial loss of function can lead to diseases such as muscular dystrophy.

In the nematode C. elegans, as in humans, mutations in basement membrane components can be lethal. New work published in GENETICS by Gotenstein et al. shows that this lethality can be rescued by mutations in certain membrane structural components. Worms, like other animals, rely on enzymes called peroxidasins to crosslink basement membrane constituents and thus increase their structural integrity. This crosslinking is critical during development; disabling the peroxidasin PXN-2, for example, prevents worms from surviving beyond the embryonic or larval stage.

Unexpectedly, Gotenstein et al. discovered that gain-of-function mutations in a few proteins that make up the basement membrane itself, including perlecan and type IV collagen, can prevent the dysfunctions caused by pxn-2 mutations. Mutations that affect part of the extracellular domain of LET-805, a transmembrane protein thought to help the basement membrane adhere to the epidermis, also suppressed the mutant phenotype. Mutations that suppressed the phenotype of pxn-2 mutants also restored normal development in worms with mutations in spon-1, which is also important for basement membrane assembly.

SPON-1’s precise role in basement membrane formation isn’t fully understood, but its molecular mechanism is thought to be different from that of PXN-2, implying that the newly discovered suppressor mutations affect the basement membrane broadly, rather than being narrowly involved in individual pathways. The unanticipated flexibility in the formation of the basement membrane offers a new perspective on this vital, highly conserved structure, unlocking a new realm of possible mechanisms to explore.